Early treatment of biotin-thiamine-responsive basal ganglia disease improves the prognosis.

BACKGROUND: Biotin-thiamine-responsive basal ganglia disease (BTBGD) is an autosomal recessive neurometabolic disorder associated with pathogenic variants in SLC19A3 gene. The clinical picture includes symptoms of subacute encephalopathy (e.g. confusion, dysphagia, dysarthria, and seizures), which respond very well to early treatment with thiamine and biotin. METHOD: A retrospective review of clinical characteristics, magnetic resonance imaging and molecular findings in 3 patients with BTBGD. RESULTS: The first symptoms in all patients occurred at 12-24 months of age and they had subacute encephalopathy, ataxia and dystonia. The baseline magnetic resonance imaging demonstrated abnormal signal intensity in the basal ganglia with atrophy and necrosis of the basal ganglia during follow-up in two patients. One patient was diagnosed and the treatment was initiated after a long period from symptoms onset and he is currently severely affected, with dystonia, quadriparesis and seizures. The other two patients were diagnosed early in life and are currently stable on treatment, without the clinical symptoms. Genetic testing demonstrated pathogenic variants in SLC19A3 gene. CONCLUSION: To avoid diagnostic errors and delayed or incorrect treatment, BTBGD must be recognized early. Adequate prompt treatment gives the chance of significant clinical improvement. Unexplained encephalopathy and MRI abnormalities including bilateral abnormal signal in the basal ganglia should alert the clinician to consider BTBGD in the differential, and the treatment with biotin and thiamine should be introduced immediately.

Positronium imaging with the novel multiphoton PET scanner.

In vivo assessment of cancer and precise location of altered tissues at initial stages of molecular disorders are important diagnostic challenges. Positronium is copiously formed in the free molecular spaces in the patient's body during positron emission tomography (PET). The positronium properties vary according to the size of inter- and intramolecular voids and the concentration of molecules in them such as, e.g., molecular oxygen, O2; therefore, positronium imaging may provide information about disease progression during the initial stages of molecular alterations. Current PET systems do not allow acquisition of positronium images. This study presents a new method that enables positronium imaging by simultaneous registration of annihilation photons and deexcitation photons from pharmaceuticals labeled with radionuclides. The first positronium imaging of a phantom built from cardiac myxoma and adipose tissue is demonstrated. It is anticipated that positronium imaging will substantially enhance the specificity of PET diagnostics.

Advanced Monte Carlo simulations of emission tomography imaging systems with GATE.

Built on top of the Geant4 toolkit, GATE is collaboratively developed for more than 15 years to design Monte Carlo simulations of nuclear-based imaging systems. It is, in particular, used by researchers and industrials to design, optimize, understand and create innovative emission tomography systems. In this paper, we reviewed the recent developments that have been proposed to simulate modern detectors and provide a comprehensive report on imaging systems that have been simulated and evaluated in GATE. Additionally, some methodological developments that are not specific for imaging but that can improve detector modeling and provide computation time gains, such as Variance Reduction Techniques and Artificial Intelligence integration, are described and discussed.

The frequency of mitochondrial polymerase gamma related disorders in a large Polish population cohort.

Diseases related to DNA polymerase gamma dysfunction comprise of heterogeneous clinical presentations with variable severity and age of onset. Molecular screening for the common POLG variants: p.Ala467Thr, p.Trp748Ser, p.Gly848Ser, and p.Tre251Ile has been conducted in a large population cohort (n = 3123) and in a clinically heterogeneous group of 1289 patients. Recessive pathogenic variants, including six novel ones were revealed in 22/26 patients. Infantile Alpers-Huttenlocher syndrome and adulthood ataxia spectrum were the most common found in our group. Distinct molecular profile identified in the Polish patients with significant predominance of p.Trp748Ser variant (50% of mutant alleles) reflected strikingly low population frequency of the three remaining variants and slightly higher p.Trp748Ser allele frequency in the general Polish population as compared to the non-Finish European population.

Pathology of skeletal muscle fibers and small blood vessels in MERRF syndrome: an ultrastructural study.

Our studies concerned skeletal muscle biopsy specimens from a patient with clinically suspected MERRF syndrome, confirmed by genetic tests showing the presence of point mutation in the m.8344A> G in the tRNALys gene. Ultrastructurally, extensive damage of mitochondria in skeletal muscle fibres was observed, including the presence of two types of mitochondrial inclusions. Mild damage of mitochondria was revealed in small blood vessels and the presence of calcium deposits in the vascular walls were observed. The differences in mitochondrial damage may be related to different origin and expenditure of biologically useful energy in these cells.

Novel scintillating material 2-(4-styrylphenyl)benzoxazole for the fully digital and MRI compatible J-PET tomograph based on plastic scintillators.

A novel plastic scintillator is developed for the application in the digital positron emission tomography (PET). The novelty of the concept lies in application of the 2-(4-styrylphenyl)benzoxazole as a wavelength shifter. The substance has not been used as scintillator dopant before. A dopant shifts the scintillation spectrum towards longer wavelengths making it more suitable for applications in scintillators of long strips geometry and light detection with digital silicon photomultipliers. These features open perspectives for the construction of the cost-effective and MRI-compatible PET scanner with the large field of view. In this article we present the synthesis method and characterize performance of the elaborated scintillator by determining its light emission spectrum, light emission efficiency, rising and decay time of the scintillation pulses and resulting timing resolution when applied in the positron emission tomography. The optimal concentration of the novel wavelength shifter was established by maximizing the light output and it was found to be 0.05 ‰ for cuboidal scintillator with dimensions of 14 mm x 14 mm x 20 mm.

Coexistence of mutations in keratin 10 (KRT10) and the mitochondrial genome in a patient with ichthyosis with confetti and Leber's hereditary optic neuropathy.

Ichthyosis with confetti (IWC) is a severe congenital genodermatosis characterized by ichthyosiform erythroderma since birth and confetti-like spots of normal skin appearing in childhood as a results of revertant mosaicism. This disorder is caused by mutations in KRT10 or KRT1 genes. We report a 16-year-old boy who presented ichthyosiform erythroderma with severe desquamation since birth and gradually worsening psycho-neurological symptoms (mental retardation, ataxia, dystonia, hypoacusis). The patient conspicuously lacked typical confetti-like spots at the age of 16. The molecular diagnostics by the whole exome sequencing showed a novel de novo (c.1374-2A>C) mutation in the KRT10 gene responsible for the development of IWC (KRT10 defect was confirmed by immunofluorescent study). Concurrently, the m.14484T>C mutation in mitochondrial MTND6 gene (characteristic for Leber's hereditary optic neuropathy or LHON) was detected in patient, his mother and brother. LHON causes frequent inherited blindness typically appearing during young adult life whose expression can be triggered by additional factors such as smoking or alcohol exposure. We speculate the effects of KRT10 and LHON mutations influence each other-skin inflammatory reaction due to severe ichthyosis might trigger the development of psychoneurological abnormalities whereas the mitochondrial mutation may reduce revertant mosaicism phenomenon resulting in the lack of confetti-like spots characteristic for IWC. However, based on a single case we should be cautious about attributing phenotypes to digenic mechanisms without functional data.

Modulation of mitochondrial dysfunction-related oxidative stress in fibroblasts of patients with Leigh syndrome by inhibition of prooxidative p66Shc pathway.

The mitochondrial respiratory chain, and in particular, complex I, is a major source of reactive oxygen species (ROS) in cells. Elevated levels of ROS are associated with an imbalance between the rate of ROS formation and the capacity of the antioxidant defense system. Increased ROS production may lead to oxidation of DNA, lipids and proteins and thus can affect fundamental cellular processes. The aim of this study was to investigate the magnitude of intracellular oxidative stress in fibroblasts of patients with Leigh syndrome with defined mutations in complex I. Moreover, we hypothesized that activation of the p66Shc protein (phosphorylation of p66Shc at Ser36 by PKCß), being part of the oxidative stress response pathway, is partially responsible for the increased ROS production in cells with dysfunctional complex I. Characterization of bioenergetic parameters and ROS production showed that the cellular model of Leigh syndrome is described by increased intracellular oxidative stress and oxidative damage to DNA and proteins, which correlate with increased p66Shc phosphorylation at Ser36. Treatment of patients' fibroblasts with hispidin (an inhibitor of the protein kinase PKCß), in addition to decreasing ROS production and intracellular oxidative stress, resulted in restoration of complex I activity.

Cardiac autonomic function in type 1 and type 2 myotonic dystrophy.

OBJECTIVE: The aim of this study was to evaluate cardiac autonomic nervous system function using Holter-derived and standard electrocardiographic parameters in patients with myotonic dystrophy (dystrophia myotonica, DM) and no clinically overt heart involvement. METHODS: Eighty-four DM patients without conditions potentially influencing cardiac autonomic function were enrolled in the study: 44 with DM type 1 and 40 with DM type 2 (mean age 34.9 ± 11.5 and 47.8 ± 13.5 years, respectively). Two corresponding control groups of aged-matched healthy subjects were selected for DM1 (n = 35) and for DM2 (n = 30). Standard electrocardiography for QT interval dispersion and 24-h Holter monitoring with time-domain heart rate variability and heart rate turbulence were performed. RESULTS: No significant differences in time-domain heart rate variability parameters between DM1 or DM2 subjects and controls were observed. However, heart rate turbulence parameters were significantly impaired in DM1 patients as compared to their controls: turbulence onset (p = 0.025), and turbulence slope (p = 0.018). Moreover, turbulence slope was also impaired in DM2 patients (p = 0.042). As compared to controls, we observed an increased QT dispersion, both in DM1 (p = 0.003) and also in DM2 patients (p < 0.0001). No relationship between disease duration or neurological status and time-domain heart rate variability, heart rate turbulence, and QT dispersion was observed. INTERPRETATION: Despite normal time-domain heart rate parameters, impaired heart rate turbulence and increased QT dispersion may suggest cardiac autonomic nervous system dysfunction in DM patients. The present study is the first one in which heart rate turbulence and QT dispersion assessment were examined both in DM1 and DM2 patients.

Natural and synthetic vocalizations of brown rat pups, Rattus norvegicus, enhance attractiveness of bait boxes in laboratory and field experiments.

BACKGROUND: Rats are often neophobic and thus do not readily enter trap boxes which are mandated in rodent management to help reduce the risk of accidental poisoning or capture of non-target animals. Working with brown rats, Rattus norvegicus, as a model species, our overall objective was to test whether sound cues from pups could be developed as a means to enhance captures of rats in trap boxes. RESULTS: Recording vocalizations from three-day-old pups after removal from their natal nest with both sonic and ultrasonic microphones revealed frequency components in the sonic range (1.8-7.5 kHz) and ultrasonic range (18-24 kHz, 33-55 kHz, 60-96 kHz). In two-choice laboratory bioassays, playback recordings of these vocalizations induced significant phonotactic and arrestment responses by juvenile, subadult and adult female and male rats. The effectiveness of engineered 'synthetic' rat pup sounds was dependent upon their frequency components, sound durations and the sound delivery system. Unlike other speakers, a piezoelectric transducer emitting sound bursts of 21 kHz with a 63-KHz harmonic, and persisting for 20-300 ms, proved highly effective in attracting and arresting adult female rats. In a field experiment, a battery-powered electronic device fitted with a piezoelectric transducer and driven by an algorithm that randomly generated sound cues resembling those recorded from rat pups and varying in fundamental frequency (19-23 kHz), duration (20-300 ms) and intermittent silence (300-5000 ms) significantly enhanced captures of rats in trap boxes baited with a food lure and soiled bedding material of adult female rats. CONCLUSION: Our study provides proof of concept that rat-specific sound cues or signals can be effectively reproduced and deployed as a means to enhance capture of wild rats. © 2016 Society of Chemical Industry.

No Evidence for Association of SCO2 Heterozygosity with High-Grade Myopia or Other Diseases with Possible Mitochondrial Dysfunction.

SCO2 mutations cause recessively inherited cytochrome c oxidase deficiency. Recently Tran-Viet et al. proposed that heterozygosity for pathogenic SCO2 variants, including the common E140K variant, causes high-grade myopia. To investigate the association of SCO2 mutations with myopia, ophthalmic examinations were performed on 35 E140K carriers, one homozygous infant, and on a mouse model of Sco2 deficiency. Additionally, a screen for other putative effects of SCO2 heterozygosity was carried out by comparing the prevalence of the common E140K variant in a population of patients with undiagnosed diseases compatible with SCO2-related pathogenesis to that in a general population sample. High-grade myopia was not identified in any of the studied individuals. Of the carriers, 17 were emmetropic, and 18 possessed refractive errors. Additionally, no significant axial elongation indicative of high-grade myopia was found in mice carrying E129K (corresponding to E140K in humans) knock-in mutations. The prevalence of E140K carriers in the symptomatic cohort was evaluated as 1:103 (CI: 0.44-2.09) and did not differ significantly from the population prevalence (1:147, CI: 0.45-1.04).Our study demonstrates that heterozygosity for pathogenic SCO2 variants is not associated with high-grade myopia in either human patients or in mice.

Does scoliosis-specific exercise treatment in adolescence alter adult quality of life?

OBJECTIVE: Health-related quality of life in adults, who in adolescence participated in a scoliosis-specific exercise program, was not previously studied. Design. Cross-sectional study, with retrospective data collection. MATERIAL AND METHODS: Homogenous groups of 68 persons (43 women) aged 30.10 (25-39) years, with mild or moderate scoliosis, and 76 (38 women) able-bodied persons, aged 30.11 (24-38) years, who 16.5 (12-26) years earlier had completed scoliosis-specific exercise or observation regimes, participated. Their respiratory characteristics did not differ from predicted values. The WHOQOL-BREF questionnaire, Oswestry Disability Questionnaire, and pain scale (VAS) were applied. RESULTS: The transformed WHOQOL-BREF scores ranged from 54.6 ± 11.19 in the physical domain in the mild scoliotic subgroup to 77.1 ± 16.05 in the social domain in the able-bodied subgroup. The ODQ values did not generally exceed 5.3 ± 7.53. Inter- and intragroup differences were nonsignificant. Age, marital status, education, and gender were significantly associated with the ODQ scores. Significant association between the ODQ and WHOQOL-BREF social relationships domain scores with the participation in exercise treatment was found. CONCLUSIONS: Participants with the history of exercise treatment generally did not differ significantly from their peers who were only under observation. This study cannot conclude that scoliosis-specific exercise treatment in adolescence alters quality of life in adulthood.

The natural history of SCO2 deficiency in 36 Polish children confirmed the genotype-phenotype correlation.

The aim of this study was to assess the natural history of the SCO2 deficiency in relation to the genotype in a cohort of 62 patients with SCO2 mutations (36 this study, 26 previous reports). A novel, milder phenotype (disease onset delayed until one year after birth, nonspecific encephalomyopathy, and 2-4 year survival period) associated with compound heterozygosity of the common p.E140K and a novel p.M177T mutations extends the range of symptoms of the SCO2 deficiency. The prevalence of SCO2 deficiency in Poland is relatively high. A search for SCO2 mutations in patients with histology resembling SMA appears to efficiently improve the detection rate.

Molecular investigations of mitochondrial deletions: evaluating the usefulness of different genetic tests.

Deletions in mitochondrial DNA are a common cause of mitochondrial disorders. The molecular diagnosis of mtDNA deletions for years was based on Southern hybridization later replaced by PCR methods such as PCR with primers specific for a particular deletion (mainly the so-called common deletion of 4977 bp) and long PCR. In order to evaluate the usefulness of MLPA (Multiplex Ligation-dependent Probe Amplification) in molecular diagnosis of large scale mtDNA deletions we compare four diagnostic methods: Southern hybridization, PCR, long-PCR and MLPA in a group of 16 patients with suspected deletions. Analysis was performed on blood, muscle and in one case hepatic tissue DNA. The MLPA was not able to confirm all the deletions detected by PCR methods, but due to its relative ease of processing, minimal equipment, low costs and the additional possibility to detect frequent point mtDNA mutations in one assay it is worth considering as a screening method. We recommend to always confirm MLPA results by PCR methods.

Variations in bioelectric activity during symmetric loading and asymmetric stretching of paraspinal extensors in young adult women with mild single curve scoliosis.

INTRODUCTION: Symmetrical loading and asymmetrical stretching of trunk extensors are applied in scoliosis physiotherapy management. Conflicting evidence is available on trunk erectors' bioelectrical activity during such static exercise, especially in adult subjects. Our purpose was to identify the profile of bioelectrical activity of trunk extensors during static contractions against symmetrical loading with body mass in young adult females with single curve scoliosis, who participated in adolescence in a scoliosis-specific physiotherapy program. MATERIAL AND METHODS: Thirty five females, aged 30.6±2.7 years, with body weight of 56.8±4.4 kgs and height 1.64±0.05 m with single curve thoracic scoliosis, 11-36° Cobb, who in adolescence had attended a scoliosis-specific physiotherapy program, participated. Braced and/or surgically treated subjects were excluded. Characteristics of the integrated EMG were collected and analysed. The measurements were conducted on a subject in prone position at rest, during 20 second static symmetrical erectors' contractions while sustaining elevated trunk and during the same effort, while stretching trunk erectors on the concave side of the curve by extending and reaching the corresponding arm forward. RESULTS: The biopotentials measured on both sides of the spine differed significantly (p<.001) during asymmetrical stretching of the erector muscles on the concave side while extending the trunk. We did not observe such differences in measurements obtained while at rest and during symmetrical contractions without stretching. CONCLUSIONS: We observed a beneficial scheme of muscle activity during trunk extension and stretching of the erector muscles on the concave side of the curvature in lying prone position, while extending and reaching forward an arm on the convex side. Significance. These findings could provide a useful remark for exercise prescription for adult patients with single thoracic scoliosis. However, the assumptions need wider studies.

Screening for scoliosis: different countries' perspectives and evidence-based health care.

Idiopathic scoliosis affects 2-3% of adolescents. Large, progressing deformities, mostly present in girls, may lead to pulmonary complications, pain symptoms, the feeling of social isolation, and even mental disorders. The correlation of screening programs with surgery rate reduction and the clinical effectiveness of bracing remain a matter of debate. Critics indicate overdetection, qualification for therapy of insignificant curves, unjustified treatment, and risks of psychological side effects, whereas supporters underline the need for screening, and suggest improvements. It remains unclear whether such opposite opinions are based on sound evidence. To identify relevant studies, guidelines, and recommendations, MEDLINE, Google Scholar, and Cochrane Library databases were searched. The levels of evidence presented in selected studies and grading of recommendations reported in available guidelines and recommendation statements were assessed using the SIGN scoring system. Screening programs are legislated, recommended, or not recommended in different American states. British and Canadian screening recommendations do not mention scoliosis; Australian boards recommend against scoliosis screening programs. Other publications such as Singapore, Turkish, and Malaysian publications underline the cost-effectiveness and clinical importance of the procedures. Different Greek authors postulate the benefits and harms caused by the programs to many schoolchildren. Such a polarity illustrates the topicality of the quality of scientific evidence analyses and the significance of the grading of the recommendations process. It appears that critical opinions often result from implementing such analyses, whereas those supporting the programs tend to value the importance of expert opinions.

Drug-resistant epilepsia and fulminant valproate liver toxicity. Alpers-Huttenlocher syndrome in two children confirmed post mortem by identification of p.W748S mutation in POLG gene.

BACKGROUND: POLG (polymerase gamma) gene mutations lead to a variety of neurological disorders, including Alpers-Huttenlocher syndrome (AHS). The diagnostic triad of AHS is: resistant epilepsy, liver impairment triggered by sodium valproate (VA), and mitochondrial DNA depletion. MATERIAL/METHODS: A cohort of 28 children with mitochondrial encephalopathy and liver failure was qualified for retrospective study of mitochondrial DNA depletion and POLG mutations. RESULTS: The p.W748S POLG gene mutation was revealed in 2 children, the only ones in the cohort who fulfilled the AHS criteria. Depletion of mtDNA (16% of control value) was confirmed post mortem in available liver tissue and was not detected in the muscle. The disease started with drug-resistant seizures, failure to thrive and developmental regression at the ages of 7 and 18 months, respectively. Irreversible liver failure developed after VA administration. Co-existence of epilepsy, VA liver toxicity, lactic acidemia and muscle respiratory chain dysfunction led finally to the diagnosis of mitochondrial disorder (and AHS suspicion). CONCLUSIONS: Our results confirm, for the first time, the occurrence of a pathology caused by POLG gene mutation(s) in the Polish population. POLG mutation screening and mtDNA depletion assessment should be included in differential diagnosis of drug-resistant epilepsy associated with a hepatopathy.

Post mortem identification of deoxyguanosine kinase (DGUOK) gene mutations combined with impaired glucose homeostasis and iron overload features in four infants with severe progressive liver failure.

Deoxyguanosine kinase deficiency (dGK) is a frequent cause of the hepatocerebral form of mitochondrial depletion syndrome (MDS). A group of 28 infants with severe progressive liver failure of unknown cause was recruited for post mortem search for deoxyguanosine kinase (DGUOK) gene mutations. Four affected patients (14% of the studied group), two homozygotes, one compound heterozygote, and one heterozygote, with DGUOK mutation found on only one allele, were identified. Three known pathogenic mutations in the DGUOK gene were detected, c.3G>A (p.Met1Ile), c.494A>T (p.Glu165Val), and c.766_767insGATT (p.Phe256X), and one novel molecular variant of unknown pathogenicity, c.813_814insTTT (p.Asn271_Thr272insPhe). Profound mitochondrial DNA depletion was confirmed in available specimens of the liver (4%, 15%, and 10% of the normal value) and in the muscle (4%, 23%, 45%, and 6%, respectively). The patients were born with low weights for gestational age and they presented adaptation trouble during the first days of life. Subsequently, liver failure developed, leading to death at the ages of 18, 6, 5.5, and 2.25 months, respectively. Mild neurological involvement was observed in all children (hypotonia, psychomotor retardation, and ptosis). Hypoglycemia (hypoketotic) and lactic acidosis were the constant laboratory findings. Elevated transferrin saturation, high ferritin, and alpha-fetoprotein levels resembled, in two cases, a neonatal hemochromatosis. Liver histopathology showed severe hepatic damage ranging from micronodular formation and cirrhosis to the total loss of liver architecture with diffuse fibrosis and neocholangiolar proliferation. Pancreatic islet cell hyperplasia with numerous confluent giant islets was found in both autopsied infants. Analysis of the natural history of the disease in our patients and the literature data led us to the following observations: (i) islet cell hyperplasia (and hyperinsulinism) may contribute to MDS-associated hypoglycemia; (ii) iron overload may additionally damage mtDNA-depleted tissues; (iii) low birth weight, adaptation trouble, and abnormal amino acids in newborn screening are frequent in dGK-deficient neonates.

A homozygous mutation in the SCO2 gene causes a spinal muscular atrophy like presentation with stridor and respiratory insufficiency.

UNLABELLED: Infants with deficiency of cytochrome c oxidase (COX) due to SCO2 mutations observed so far usually demonstrated early cardiomyopathy, encephalopathy and lactic acidosis. Milder spinal muscular atrophy-like (SMA-like) phenotype was also rarely reported. The aim is to present 18 Polish patients with SCO2 mutations. Molecular study revealed p.E140K mutation in all cases (on 32 alleles); p.Q53X mutation and novel p.M177T change were identified in single patients. In three families no second mutation was found. Thirteen p.E140K homozygotes presented in infancy with floppiness and remarkable stridor. Survival motor neuron (SMN) gene deletion was excluded. Mild to moderate lactic academia was found. Neurological involvement manifested as spasticity and psychomotor retardation. In some patients strabismus, ptosis and episodes of seizures were seen. During second half of the year chronic respiratory failure with artificial respiration dependency appeared in all homozygotes. Heart involvement was never present at the beginning. Rapidly progressive hypertrophic cardiomyopathy developed in several patients at the terminal stage. The stridor was constant and striking feature. Skeletal muscle biopsy was performed in 16 patients including 11 homozygotes. Four pathological patterns were discerned - from neurogenic muscle changes, including spinal muscular atrophy (SMA) to unspecific findings. Histochemical cytochrome c oxidase (COX) deficit was not a constant feature. Significant decrease in respiratory chain complex IV activity was detected in muscle homogenate by spectrophotometric method only in 7 out of 12 examined cases. CONCLUSIONS: 1/Mutations of SCO2 gene should be considered as a possible cause of neurogenic skeletal muscle features (including SMA-like) in infants with encephalomyopathy even in the absence of heart involvement and COX deficit; 2/Inspiratory stridor may be symptomatic of SCO2 gene mutation(s).